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Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition 期刊论文
NATURE, 2020, 577 (7790) : 421-+
作者:  Xue, Jenny Y.;  Zhao, Yulei;  Aronowitz, Jordan;  Mai, Trang T.;  Vides, Alberto;  Qeriqi, Besnik;  Kim, Dongsung;  Li, Chuanchuan;  de Stanchina, Elisa;  Mazutis, Linas;  Risso, Davide;  Lito, Piro
收藏  |  浏览/下载:34/0  |  提交时间:2020/07/03

KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma(1,2). KRAS(G12C) inhibitors(3,4) are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation(4-6), and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.


  
A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity 期刊论文
NATURE, 2020, 577 (7790) : 416-+
作者:  Morley, Jessica;  Cowls, Josh;  Taddeo, Mariarosaria;  Floridi, Luciano
收藏  |  浏览/下载:35/0  |  提交时间:2020/07/03

Humoral immune responses to immunization and infection and susceptibilities to antibody-mediated autoimmunity are generally lower in males(1-3). However, the mechanisms underlying such sexual dimorphism are not well understood. Here we show that there are intrinsic differences between the B cells that produce germinal centres in male and female mice. We find that antigen-activated male B cells do not position themselves as efficiently as female B cells in the centre of follicles in secondary lymphoid organs, in which germinal centres normally develop. Moreover, GPR174-an X-chromosome-encoded G-protein-coupled receptor-suppresses the formation of germinal centres in male, but not female, mice. This effect is intrinsic to B cells, and correlates with the GPR174-enhanced positioning of B cells towards the T-cell-B-cell border of follicles, and the distraction of male, but not female, B cells from S1PR2-driven follicle-centre localization. Biochemical fractionation of conditioned media that induce B-cell migration in a GPR174-dependent manner identifies CCL21 as a GPR174 ligand. In response to CCL21, GPR174 triggers a calcium flux and preferentially induces the migration of male B cells  GPR174 also becomes associated with more G alpha i protein in male than in female B cells. Male B cells from orchidectomized mice exhibit impaired GPR174-mediated migration to CCL21, and testosterone treatment rescues this defect. Female B cells from testosterone-treated mice exhibit male-like GPR174-G alpha i association and GPR174-mediated migration. Deleting GPR174 from male B cells causes more efficient positioning towards the follicular centre, the formation of more germinal centres and an increased susceptibility to B-cell-dependent experimental autoimmune encephalomyelitis. By identifying GPR174 as a receptor for CCL21 and demonstrating its sex-dependent control of B-cell positioning and participation in germinal centres, we have revealed a mechanism by which B-cell physiology is fine-tuned to impart sexual dimorphism to humoral immunity.


  
Childhood vaccines and antibiotic use in low- and middle-income countries 期刊论文
NATURE, 2020, 581 (7806) : 94-+
作者:  Louca, Stilianos;  Pennell, Matthew W.
收藏  |  浏览/下载:29/0  |  提交时间:2020/07/03

Vaccines may reduce the burden of antimicrobial resistance, in part by preventing infections for which treatment often includes the use of antibiotics(1-4). However, the effects of vaccination on antibiotic consumption remain poorly understood-especially in low- and middle-income countries (LMICs), where the burden of antimicrobial resistance is greatest(5). Here we show that vaccines that have recently been implemented in the World Health Organization'  s Expanded Programme on Immunization reduce antibiotic consumption substantially among children under five years of age in LMICs. By analysing data from large-scale studies of households, we estimate that pneumococcal conjugate vaccines and live attenuated rotavirus vaccines confer 19.7% (95% confidence interval, 3.4-43.4%) and 11.4% (4.0-18.6%) protection against antibiotic-treated episodes of acute respiratory infection and diarrhoea, respectively, in age groups that experience the greatest disease burden attributable to the vaccine-targeted pathogens(6,7). Under current coverage levels, pneumococcal and rotavirus vaccines prevent 23.8 million and 13.6 million episodes of antibiotic-treated illness, respectively, among children under five years of age in LMICs each year. Direct protection resulting from the achievement of universal coverage targets for these vaccines could prevent an additional 40.0 million episodes of antibiotic-treated illness. This evidence supports the prioritization of vaccines within the global strategy to combat antimicrobial resistance(8).


Pneumococcal and rotavirus vaccines have reduced antibiotic consumption substantially among children under five years old in low- and middle-income countries  however, this effect could be doubled if all countries were to implement vaccination programmes and meet universal vaccine coverage targets.


  
Preparation of cyclohexene isotopologues and stereoisotopomers from benzene 期刊论文
NATURE, 2020, 581 (7808) : 288-+
作者:  Shimazaki, Yuya;  Schwartz, Ido;  Watanabe, Kenji;  Taniguchi, Takashi;  Kroner, Martin;  Imamoglu, Atac
收藏  |  浏览/下载:36/0  |  提交时间:2020/07/03

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine(1). Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules(1). Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington'  s disease(2), was recently approved by the United States'  Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial(1,3,4). The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound(5), improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug(6,7), these processes are often unselective and the stereoisotopic purity can be difficult to measure(7,8). Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.


Cyclohexene isotopologues and stereoisotopomers with varying degrees of deuteration are formed by binding a tungsten complex to benzene, which facilitates the selective incorporation of deuterium into any position on the ring.


  
The fate of carbon in a mature forest under carbon dioxide enrichment 期刊论文
NATURE, 2020, 580 (7802) : 227-+
作者:  Sun, P. Z.;  Yang, Q.;  Kuang, W. J.;  Stebunov, Y. V.;  Xiong, W. Q.;  Yu, J.;  Nair, R. R.;  Katsnelson, M. I.;  Yuan, S. J.;  Grigorieva, I. V.;  Lozada-Hidalgo, M.;  Wang, F. C.;  Geim, A. K.
收藏  |  浏览/下载:91/0  |  提交时间:2020/05/13

Carbon dioxide enrichment of a mature forest resulted in the emission of the excess carbon back into the atmosphere via enhanced ecosystem respiration, suggesting that mature forests may be limited in their capacity to mitigate climate change.


Atmospheric carbon dioxide enrichment (eCO(2)) can enhance plant carbon uptake and growth(1-5), thereby providing an important negative feedback to climate change by slowing the rate of increase of the atmospheric CO2 concentration(6). Although evidence gathered from young aggrading forests has generally indicated a strong CO2 fertilization effect on biomass growth(3-5), it is unclear whether mature forests respond to eCO(2) in a similar way. In mature trees and forest stands(7-10), photosynthetic uptake has been found to increase under eCO(2) without any apparent accompanying growth response, leaving the fate of additional carbon fixed under eCO(2) unclear(4,5,7-11). Here using data from the first ecosystem-scale Free-Air CO2 Enrichment (FACE) experiment in a mature forest, we constructed a comprehensive ecosystem carbon budget to track the fate of carbon as the forest responded to four years of eCO(2) exposure. We show that, although the eCO(2) treatment of +150 parts per million (+38 per cent) above ambient levels induced a 12 per cent (+247 grams of carbon per square metre per year) increase in carbon uptake through gross primary production, this additional carbon uptake did not lead to increased carbon sequestration at the ecosystem level. Instead, the majority of the extra carbon was emitted back into the atmosphere via several respiratory fluxes, with increased soil respiration alone accounting for half of the total uptake surplus. Our results call into question the predominant thinking that the capacity of forests to act as carbon sinks will be generally enhanced under eCO(2), and challenge the efficacy of climate mitigation strategies that rely on ubiquitous CO2 fertilization as a driver of increased carbon sinks in global forests.


  
Gut stem cell necroptosis by genome instability triggers bowel inflammation 期刊论文
NATURE, 2020, 580 (7803) : 386-+
作者:  Xing, Lida;  39;Connor, Jingmai K.
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

The aetiology of inflammatory bowel disease (IBD) is a multifactorial interplay between heredity and environment(1,2). Here we report that deficiency in SETDB1, a histone methyltransferase that mediates the trimethylation of histone H3 at lysine 9, participates in the pathogenesis of IBD. We found that levels of SETDB1 are decreased in patients with IBD, and that mice with reduced SETDB1 in intestinal stem cells developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability(3), and the loss of SETDB1 in intestinal stem cells released repression of endogenous retroviruses (retrovirus-like elements with long repeats that, in humans, comprise approximately 8% of the genome). Excessive viral mimicry generated by motivated endogenous retroviruses triggered Z-DNA-binding protein 1 (ZBP1)-dependent necroptosis, which irreversibly disrupted homeostasis of the epithelial barrier and promoted bowel inflammation. Genome instability, reactive endogenous retroviruses, upregulation of ZBP1 and necroptosis were all seen in patients with IBD. Pharmaceutical inhibition of RIP3 showed a curative effect in SETDB1-deficient mice, which suggests that targeting necroptosis of intestinal stem cells may represent an approach for the treatment of severe IBD.


  
Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8(+) cells 期刊论文
NATURE, 2020, 578 (7793) : 154-+
作者:  Diaz-Cuadros, Margarete;  Wagner, Daniel E.;  Budjan, Christoph;  Hubaud, Alexis;  Tarazona, Oscar A.;  Donelly, Sophia;  Michaut, Arthur;  Al Tanoury, Ziad;  Yoshioka-Kobayashi, Kumiko;  Niino, Yusuke;  Kageyama, Ryoichiro;  Miyawaki, Atsushi;  Touboul, Jonathan;  Pourquie, Olivier
收藏  |  浏览/下载:46/0  |  提交时间:2020/07/03

Human immunodeficiency virus (HIV) persists indefinitely in individuals with HIV who receive antiretroviral therapy (ART) owing to a reservoir of latently infected cells that contain replication-competent virus(1-4). Here, to better understand the mechanisms responsible for latency persistence and reversal, we used the interleukin-15 superagonist N-803 in conjunction with the depletion of CD8(+) lymphocytes in ART-treated macaques infected with simian immunodeficiency virus (SIV). Although N-803 alone did not reactivate virus production, its administration after the depletion of CD8(+) lymphocytes in conjunction with ART treatment induced robust and persistent reactivation of the virus in vivo. We found viraemia of more than 60 copies per ml in all macaques (n = 14  100%) and in 41 out of a total of 56 samples (73.2%) that were collected each week after N-803 administration. Notably, concordant results were obtained in ART-treated HIV-infected humanized mice. In addition, we observed that co-culture with CD8(+) T cells blocked the in vitro latency-reversing effect of N-803 on primary human CD4(+) T cells that were latently infected with HIV. These results advance our understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection.


The interleukin-15 superagonist N-803, combined with the depletion of CD8(+) lymphocytes, induced a robust and persistent reactivation of the virus in vivo in both antiretroviral-therapy-treated SIV-infected macaques and HIV-infected humanized mice.


  
Systemic HIV and SIV latency reversal via non-canonical NF-kappa B signalling in vivo 期刊论文
NATURE, 2020, 578 (7793) : 160-+
作者:  Momcilovic, Milica;  Jones, Anthony;  Bailey, Sean T.;  Waldmann, Christopher M.;  Li, Rui;  Lee, Jason T.;  Abdelhady, Gihad;  Gomez, Adrian;  Holloway, Travis;  Schmid, Ernst;  Stout, David;  Fishbein, Michael C.;  Stiles, Linsey;  Dabir, Deepa V.;  Dubinett, Steven M.;  Christofk, Heather;  Shirihai, Orian;  Koehler, Carla M.;  Sadeghi, Saman;  Shackelford, David B.
收藏  |  浏览/下载:40/0  |  提交时间:2020/07/03

Activation of the non-canonical NF-kappa B signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of antiretroviral-therapy-treated humanized mice and rhesus macaques.


Long-lasting, latently infected resting CD4(+) T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir(1). Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect(2-9). Here we show that activation of the non-canonical NF-kappa B signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow-liver-thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4(+) T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal-in combination with appropriate tools for systemic clearance of persistent HIV infection-greatly increases opportunities for HIV eradication.


  
Impact of green control techniques on family farms' welfare 期刊论文
ECOLOGICAL ECONOMICS, 2019, 161: 91-99
作者:  Gao, Yang;  Niu, Ziheng;  Yang, Haoran;  Yu, Lili
收藏  |  浏览/下载:16/0  |  提交时间:2019/11/27
Green Control Techniques  Welfare Effect  Endogenous Switching Regression Model  Multinomial Treatment Effects Model  
Assessing the effectiveness of Japan's community-based direct payment scheme for hilly and mountainous areas 期刊论文
ECOLOGICAL ECONOMICS, 2019, 160: 62-75
作者:  Ito, Junichi;  Feuer, Hart N.;  Kitano, Shinichi;  Asahi, Haruka
收藏  |  浏览/下载:307/0  |  提交时间:2019/11/26
Direct payment scheme  Farmland abandonment  Adverse selection  Treatment effect model